Immunologic Treatment of Cancer

Abstract

Provided herein are new compositions, methods, and devices to treat cancer through a combination of immunologic chemotherapeutic agents and ablation techniques. These compositions can include immune checkpoint inhibitors, cytokines and nucleic acid drugs that aid in eliciting an immune response to treat the tumor. The administration of these compositions in addition to various ablating techniques provides a presentation of the cancer cell antigens to the immune system and the immunologic targeting of the cancer.

1 . (canceled) 
     
     
         2 . A method of treating a tumor in a patient, comprising administering to the patient intratumorally a composition comprising a combination of at least two immune checkpoint inhibitors and at least one cytokine, each being present in the composition in therapeutically effective amounts, and a pharmaceutically acceptable carrier, in an amount sufficient to treat the tumor, wherein the at least two checkpoint inhibitors are a CTLA-4 inhibitor and a PD-1 inhibitor, and wherein the at least one cytokine is GM-CSF; and
 ablating at least a portion of the tumor, thereby creating a zone of lesion, wherein the ablating results in destruction of cell membranes of cells of the tumor and exposure of intracellular components and membrane antigens.   
     
     
         3 . The method of  claim 2 , comprising ablating the tumor using cryo-ablation. 
     
     
         4 . The method of  claim 2 , comprising ablating the tumor using RF-EMB type ablation. 
     
     
         5 . The method of  claim 2 , comprising administering the composition to the patient using an injection device comprising multiple tines. 
     
     
         6 . The method of  claim 2 , comprising administering the composition using a probe, in which the probe comprises a pump to control a speed with which the composition is administered to the patient. 
     
     
         7 . The method of  claim 6 , comprising testing a location of the probe by administering an intratumoral test injection using the probe and measuring an intratumoral pressure during the test injection. 
     
     
         8 . The method of  claim 2 , in which the composition comprises an immunostimulant. 
     
     
         9 . The method of  claim 2 , in which the composition comprises an immunomodulator. 
     
     
         10 . The method of  claim 2 , in which the composition comprises a pharmaceutically acceptable carrier. 
     
     
         11 . The method of  claim 2 , in which the composition comprises an absorption delaying agent. 
     
     
         12 . The method of  claim 2 , in which the composition is provided in a controlled release formulation. 
     
     
         13 . The method of  claim 2 , comprising treating the patient using surgery, chemotherapy, immunotherapy, gene therapy, or radiation therapy before, during, or after administration of the composition to the patient. 
     
     
         14 . The method of  claim 2 , wherein the ablation is performed such that intracellular components and membrane antigens of the cells are not denatured by the ablation. 
     
     
         15 . The method of  claim 2 , comprising administering subcutaneously to the patient a therapeutically effective amount of a second cytokine after ablating the tumor, wherein the second cytokine is the same or different from the first cytokine. 
     
     
         16 . The method of  claim 2 , comprising, after the intratumoral administration of the composition, administering a second composition to the patient intravenously. 
     
     
         17 . The method of  claim 16 , in which the composition and the second composition have the same a combination of immune checkpoint inhibitors and cytokine. 
     
     
         18 . The method of  claim 2 , wherein the composition is injected in a single dose or in more than one dose. 
     
     
         19 . The method of  claim 2 , wherein the composition comprises the CTLA-4 inhibitor at a concentration of approximately 0.5 to 10 mg/ml, the PD-1 inhibitor at a concentration of approximately 0.5 to 20 mg/ml, and the GM-CSF at a concentration of approximately 10 to 500 μg/ml. 
     
     
         20 . The method of  claim 2 , wherein the composition further comprises a cytokine selected from the group consisting of IL-12, IL-6, IL-4, IL-2, TNF, IFNγ, IFNα, and any combination thereof. 
     
     
         21 . The method of  claim 2 , wherein the composition further comprises an inhibitor selected from the group consisting of an inhibitor of CD137, CD134, KIR, LAG-3, PD-L1, B7.1, B7H3, CCRY, OX-40, CD40, and any combination thereof. 
     
     
         22 . The method of  claim 2 , wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab and the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, pidilizumab, MK-3475, and MED 14736.